Life Sciences 78 (2005) 506 – 511

www.elsevier.com/locate/lifescie

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Screening the receptorome for plant-based psychoactive compounds

Kerry Ann O’Connor a, Bryan L. Roth a,b,c,*
a
Department of Biochemistry, Case Western Reserve University, Cleveland, OH, USA
b
Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA
c
Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA

Abstract

Throughout time, humans have used psychoactive plants and plant-derived products for spiritual, therapeutic and recreational purposes.
Furthermore, the investigation of psychoactive plants such as Cannabis sativa (marijuana), Nicotiana tabacum (tobacco) and analogues of
psychoactive plant derivatives such as lysergic acid diethylamide (LSD) have provided insight into our understanding of neurochemical processes
and diseases of the CNS. Currently, many of these compounds are being used to treat a variety of diseases, such as depression and anxiety in the
case of Piper methysticum Kava Kava (Martin et al., 2002; Singh and Singh, 2002). G-protein coupled receptors (GPCRs) are the most common
molecular target for both psychoactive drugs and pharmaceuticals. The ‘‘receptorome’’ (that portion of the genome encoding ligand reception)
encompasses more than 8% of the human genome (Roth et al., 2004) and as such provides a large number of possible targets for psychoactive drug
interactions. A systematic, comprehensive study is necessary to identify novel active psychoactive plant-based compounds and the molecular
targets of known compounds. Herein we describe the development of a high throughput system (HTS) to screen psychoactive compounds against
the receptorome and present two examples (Salvia divinorum, the ‘‘magic mint’’ hallucinogen and Banisteriopsis caapi, the main component of
Ayahuasca, a psychoactive beverage) where HTS enabled the identification of the molecular target of each compound.
D 2005 Elsevier Inc. All rights reserved.

Keywords: GPCR; Salvinorin A; Ayahuasca

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
The receptorome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Receptoromics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Virtual screening of the receptorome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Physical screening of the receptorome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Molecular targets of naturally occurring psychoactive-compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Salvia divinorum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Banisteriopsis caapi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

Introduction used by humans throughout time for recreational, spiritual, and

Psychoactive plants exert profound effects on human
consciousness, emotion, and cognition, and as such have been
* Corresponding author. Department of Biochemistry, Room W441, Case
Western Reserve University School of Medicine, 2109 Adelbert Road, Cleve-
land, OH 44106-4935, USA. Tel.: +1 216 368 2730; fax: +1 216 368 3419.
E-mail address: bryan.roth@case.edu (B.L. Roth).
0024-3205/$ - see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.lfs.2005.09.002
therapeutic purposes (Lewin, 1924). Cannabis sativa (mari-
juana), Papaver somniferum (opium), Coffea arabica (caf-
feine), Nicotiana tabacum (tobacco), as well as other plants
and plant-derived substances are widely used and abused at
present. Investigation of psychoactive plants and their mechan-
isms of action have provided insight into the neurochemistry of
many CNS diseases as well as the ‘‘chemistry of conscious-
ness’’ (Lewin, 1924; Nichols, 2004). The observation that
 K.A. O’Connor, B.L. Roth / Life Sciences 78 (2005) 506 – 511 507

serotonin and lysergic acid diethylamide, the analogue of ergot
alkaloids produced by Claviceps purpurae, share structural and
pharmacological properties led to the suggestion that biogenic
amines, like serotonin, were involved in mental disorders such
as schizophrenia (Gaddum and Hameed, 1954; Wooley and
Shaw, 1954). Additionally, the active ingredient in Rauwolfa
serpentina (resperine) has been shown to deplete biogenic
amines and induce depression, therefore suggesting that a lack
of serotonin and/or norepeinephrine may be the cause of this
pathology (Vertulani and Sulser, 1975). Our basic understand-
ing of mental illness as a neurochemical disease, as well as our
ability to treat these disorders has been greatly enhanced
through the study of psychoactive plants. Continued evaluation
of the molecular site of action of psychoactive drugs will
expand our list of validated targets for CNS drug discovery.
Plants and plant-derived psychoactive compounds exert
their actions via interaction with various signal transduction
molecules, either a cell surface or intracellular recognition
molecule (i.e. Freceptors_). It has recently been estimated that
¨20% of the recently completed human genome sequence is
devoted to signal transduction, and specifically receptors
(Lander et al., 2001; Venter et al., 2001). Sequencing the
genome therefore, revealed a large number of potential targets
for psychoactive drugs, and suggested the necessity of a
comprehensive, systematic approach to identifying such
targets. As summarized below, the development of high
throughput screening (HTS) tools are necessary to screen
psychoactive compounds against the receptorome.
The receptorome
Of the relatively large portion of the human genome
dedicated to signal transduction, that portion dedicated to
encoding ligand reception has been described as the ‘‘receptor-
ome’’ (Kroeze et al., 2003) and encompasses more than 8% of
the human genome (Roth et al., 2004). The receptorome is
subdivided into multiple receptor superfamilies, the largest of
which is that of the G-protein coupled receptors (GPCRs). The
GPCR superfamily accounts for approximately 3.7% of the
human genome: 735 – 802 open reading frames, of which ¨375
are neither olfactory nor taste receptors (Fredriksson et al.,
2003; Kroeze et al., 2003; Roth et al., 2004). GPCRs are the
most common molecular target for psychoactive drugs and
pharmaceuticals (Hopkins and Groom, 2002; Kroeze et al.,
2003; Lander et al., 2001; Vassilatis et al., 2003). Non-GPCR
receptors represent at least 1.5% of the genome (Venter et al.,
2001). Naturally occurring psychoactive compounds may also
produce responses via ion channels and transporters, function-
ing as ‘‘receptors,’’ which represent an additional 3% of the
genome (Roth et al., 2004; Venter et al., 2001).
Receptoromics
Virtual screening of the receptorome
Multiple computational resources currently exist to assist in
screening psychoactive compounds against the receptorome in
a virtual (in silico) manner. Bioinformatic approaches such as
BLAST have provided information on ligand:receptor interac-
tion based on consensus domain profiling and hidden Markov
models (HMM) (Gaulton and Attwood, 2003; Wise et al.,
2004). Molecular modeling has also been used to virtually
screen libraries of compounds for drug discovery efforts. For
most GPCR, this classical computational approach has utilized
homology modeling with rhodopsin (Ballesteros et al., 2001;
Palczewski et al., 2000; Shapiro et al., 2002). This model has
been quite successful in identifying molecular targets on the 5-
HT2A receptor, which interacts with many plant-derived
hallucinogens (e.g., lysergic acid amide, psilocybin, mescaline)
(Nichols, 2004; Roth et al., 2004). Molecular visualization
software such as RasMol (http://www.umass.edu/microbio/
rasmol) is another useful tool for viewing structure:function
relationships and may be accessed for free.
Multiple on-line resources for identifying molecular targets
for psychoactive botanicals also exist, and provide information
for scientists and nonscientists alike (Table 1). Both The Vaults
of Erowid (http://www.erowid.org) and The Lycaeum (http://
www.lycaeum.org) provide useful background on the chemis-
try, molecular targets, history and lore of psychoactive plants.
Although these sites are not subject to peer review, they do
provide useful information to the interested nonscientist such
as anecdotal user reports, botanical information and links to
additional articles.
Databases, such as the National Institute of Mental Health’s
Psychoactive Drug Screening Program (NIMH-PDSP) K i
Database (http://kidb.cwru.edu), allow users to quickly identify

Table 1
Representative on-line resources for screening the receptorome
Name URL Type of information
NIH Blast http://www.ncbi.nlm.nih.gov/Education/BLASTinfo/information3.html MM, S
Rasmol http://www.umass.edu/microbio/rasmol/ MM
The Vaults of Erowid http://www.erowid.org/ A,B,C,L,MT
Entheogen dot http://www.entheogen.com/ A,C,MT
The Lycaeum http://www.lycaeum.org/ A,B,C,L,MT
Botanical.com http://www.botanical.com/ B
Multidisciplinary association for psychedelic studies http://maps.org/ L
Heffter Research Institute http://www.heffter.org/ C,L,MT
NIMH-PDSP database http://kidb.cwru.edu/ C,L,MT
A = anecdotal user reports; B = botanical information; C = chemistry; L = links to articles; MM = molecular modeling or visualization; MT = molecular target; S =
sequencing information.
508 K.A. O’Connor, B.L. Roth / Life Sciences 78 (2005) 506 – 511

commonalities among drug –receptor interactions. This fully
searchable database is updated daily and currently contains
> 30,000 K i values from the literature and NIMH-PDSP
screening initiative. The K i Database is a collection of organized
tables and programs which include not only affinity values for
specific compounds screened against a large group of receptors,
but also the experimental conditions used to obtain these values
(see Roth et al., 2004 for a complete description of the K i
Database).
Physical screening of the receptorome
The identification of molecular targets of psychoactive
compounds may also be studied using direct approaches based
on ligand:receptor interactions and functional assays. Currently,
the NIMH-PDSP is the single largest collection of receptors for
which compounds may be physically screened. Traditionally,
ligand binding experiments have been used to compete a test
ligand and a receptor-specific high affinity radiolabeled ligand
using either whole cell or membrane preparations (Pert and
Snyder, 1973). This method may be utilized as a high throughput
screen because (a) multiple receptors may be probed simulta-
neously against a given ligand, and (b) binding assays allow the
use of frozen stocks of tissue or cellular membranes rather than
live specimen. However, receptor binding has many disadvan-
tages as well: (a) they do not identify the functional properties of
ligands such as antagonist, agonist, partial or inverse agonist, (b)
they do not properly assess allosteric ligands that may bind at
sites other than the primary binding site. Furthermore, their
reliance on high affinity, receptor-specific radiolabeled ligands
reduces their use in identifying orphan receptors.
Complimentary functional screens may be subsequently
performed to either validate traditional binding assays or
elucidate additional information. Due to the versatility in
GPCR signal transduction, virtually every possible signal
transduction pathway may be used to assess functional, high
throughput screening of the receptorome. These assays take
advantage of the well-characterized, diverse GPCR signaling
cascades (Table 2). Receptor and/or G-protein activation,
second-messenger production and even transcriptional activa-
tion may be assessed in a manner conducive to high
throughput screening.
HTS has also been applied to ion channel modulators and
may be helpful for studying such naturally occurring compounds
as Piper methysticum, Kava kava. This plant is though to act via
blockade of voltage-gated sodium ion channels, and calcium ion
channels. Additionally, kava has been used in the treatment of
depression and anxiety (Martin et al., 2002; Singh and Singh,
2002). Screening of calcium channel activation by various
agonists can be measured using calcium-sensitive dyes such as
those used in the Fluorescent Imaging Plate Reader (FLIPR,
Molecular Devices, Sunnyvale, CA). Recently, the Voltage/Ion
Probe Reader (VIPR, Aurora Biosciences, Indianapolis, IN) has
been modified to provide an automated screening for ion
channel modulators (Falconer et al., 2002; Gonzalez and Maher,
2002). VIPR is a versatile assay in that it may be used to identify
changes in Na+, K+, Cl , Ca++ and ligand-gated channels. It is
therefore ideal for use as a high throughput screen (> 50,000
compounds/day) for either drug discovery of analysis of
psychoactive compounds (Gonzalez and Maher, 2002).
Molecular targets of naturally occurring
psychoactive-compounds
Salvia divinorum
Salvinorin A, ‘‘the magic-mint’’ hallucinogen, is a naturally
occurring and potent hallucinogen from the sage Saliva
divinorum (Ortega et al., 1982; Valdes et al., 1984). Broad
screening of the receptorome can be appreciated in the
elucidation of the molecular target of salvinorin A. High
throughput screening profiling determined that salvinorin A
possessed high affinity and potency for the n opioid receptor
(KOR) (Roth et al., 2002). Interestingly, the specific effects of
salvinorin A were unique when compared to other hallucinogens
since it did not have appreciable affinity for either A or y opioid,
or 5-HT2A receptors (Chavkin et al., 2004; Roth et al., 2002).
Recently in vivo studies have confirmed the hypothesis that
salvinorin A exerts its effects via KOR. The nonselective
opioid antagonist, naloxone, has been reported to block its
effects in humans (Sheffler and Roth, 2003) and its effects in
nonhuman primates were shown to be equivalent to standard
KOR agonists (Butelman et al., 2004). These results may
provide insight into the pathology and treatment of diseases

Table 2
HTS functional assays based on diverse GPCR signaling and regulation
Function Assay References
G-protein activation Agonist-stimulated [35S]GTPgS binding (Asano et al., 1984; Sim et al., 1995)
GTPase activity Release of 32P-Pi from [g-32P]-GTP
Second messenger Adenylyl cyclase activity Stimulation/Inhibition of AC stimulated cAMP (Shirokova et al., 2005)
production and Intracellular Ca2+ release Fluorescent measures from PLCg driven IP3 production (Coward et al., 1999; Wise et al., 2004)
activity Ion channel activity Fluorescent measures (Falconer et al., 2002; Gonzalez and Maher, 2002)
Transcriptional activation GPCR-mediated MAPK activation (Burstein et al., 1995; Weiner et al., 2001)
Desensitization Cellular protein redistributions, enhanced cell surface (Ferguson and Caron, 2004; Milligan, 2002;
expression of WT and constitutively active GPCRs Parnot et al., 2002)
Receptor dimerization and/or FRET, BRET (Janetopoulos et al., 2001)
G-protein dissociation
AC = adenylyl cyclase; BRET = bioluminescence resonance energy transfer; FRET = fluorescence resonance energy transfer; GTP = guanosine triphosphate;
GTPase = guanosine triphosphatase; MAPK = mitogen activated protein kinase; PLC = phospholipase C.
 K.A. O’Connor, B.L. Roth / Life Sciences 78 (2005) 506 – 511
associated with altered perception (e.g., schizophrenia, Alzhei-
mer’s disease).
Banisteriopsis caapi
Ayahuasca is a South American psychotropic beverage
which is made by boiling the bark of the Banisteriopsis caapi
(Malpighiaceae) with one of various other psychotropic plants
(Dobkin de Rios, 1984; Schultes and Hofmann, 1980). This
psychotropic concoction has been used extensively in spiritual
ceremonies and for medicinal purposes in the Upper Amazon
River Basin (Schultes and Hofmann, 1982), and its use has
recently spread to Europe and North America (Dobkin de Rios,
1996). The psychotropic plants added to the B. caapi mixture,
such as Psychotria viridis (Rubiaceae), possess a potent
hallucinogen N,N-dimethyltryptamine (DMT) while B. caapi
contains beta-carbolines (e.g., harmine, harmaline, and tetra-
hydroharmine) which are highly active monoamine oxidase
(MAO) inhibitors (Rivier and Lindgren, 1972; Schultes and
Hofmann, 1980). This combination produced in ayahuasca
renders DMT, normally inactive orally due to peripheral MAO
activity (Suzuki et al., 1981), an efficacious psychoactive
compound in the presence of beta-carbolines (Ott, 1999).
DMT may then reach the brain where it acts as an agonist at
5-HT2A/2C receptors (McKenna et al., 1984; Pierce and
Peroutka, 1989).
Recent studies have revealed that ingestion of ayahuasca
produced concentration-dependent specific inhibition of MAO-
A, in liver homogenates (Schwarz et al., 2003). Furthermore,
harmine and harmaline also stimulate dopamine release in rat
striatal slices (Schwarz et al., 2003). The recent finding that
patients with Parkinson’s Disease and Parkinson’s-like symp-
toms report improvements following ingestion of ayahuasca
(Sanchez-Ramos, 1991; Serrano-Duenas et al., 2001) may
provide insight into additional natural-products-based treat-
ments for this and other diseases.
Conclusions
While several psychoactive compounds such as C. sativa
(THC), and N. tabacum (nicotine) have well-described
mechanisms of action, the molecular targets of many halluci-
nogenic plants still elude scientists (e.g., Tabernanthe iboga
and Myrstica fragens). When receptorome profiling has been
done the results have been highly informative, however this has
only been done for a few compounds (Roth et al., 2002;
Rothman et al., 2003). Due to the recently sequenced genome
and the rapid ‘‘deorphanizing’’ of many receptors, the potential
molecular targets for these compounds are rapidly growing. A
discovery-based effort seeking to elucidate these targets is
likely to be highly useful for basic scientists as well as for drug
development.
Broad, unbiased receptorome screens, such as those
described herein, may contribute to the detection of novel
drug:receptor interactions, and ligand interactions with mul-
tiple receptors. Furthermore, receptorome-wide screening of
psychoactive compounds may provide insight into novel
509
therapeutic compounds, possible side-effects of currently
marketed pharmaceuticals and a more appropriate understand-
ing of the neurochemical complexity of multifaceted diseases
(e.g., schizophrenia, Alzheimer’s disease, depression, anxiety,
drug abuse).
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